ES2256910T3 - Oral and stable pharmaceutical composition containing a replaced benzimidazol pyridilsulfinil. - Google Patents

Oral and stable pharmaceutical composition containing a replaced benzimidazol pyridilsulfinil.

Info

Publication number
ES2256910T3
ES2256910T3 ES98123251T ES98123251T ES2256910T3 ES 2256910 T3 ES2256910 T3 ES 2256910T3 ES 98123251 T ES98123251 T ES 98123251T ES 98123251 T ES98123251 T ES 98123251T ES 2256910 T3 ES2256910 T3 ES 2256910T3
Authority
ES
Spain
Prior art keywords
mixture
capsule
composition
enteric
excipient
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
ES98123251T
Other languages
Spanish (es)
Inventor
Ashok Kampal
Dilip Kumar Thacharodi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ranbaxy Laboratories Ltd
Original Assignee
Ranbaxy Laboratories Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to US8622498A priority Critical
Priority to US86224 priority
Application filed by Ranbaxy Laboratories Ltd filed Critical Ranbaxy Laboratories Ltd
Application granted granted Critical
Publication of ES2256910T3 publication Critical patent/ES2256910T3/en
Anticipated expiration legal-status Critical
Application status is Expired - Lifetime legal-status Critical

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841Filling excipients; Inactive ingredients
    • A61K9/4866Organic macromolecular compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4891Coated capsules; Multilayered drug free capsule shells

Abstract

A PHARMACEUTICAL COMPOSITION IS PRESENTED THAT IS STABLE AND ADEQUATE FOR ORAL ADMINISTRATION TO A PATIENT AND THAT INCLUDES A MIXTURE OF A SULFINYL BENCIMIDAZOLA REPLACED WITH PIRIDILE THAT HAS AN INHIBITORY ACTIVITY OF THE SECRETION OF THE GASTROLA LAZOPROZ ACID LAZOPOZ, LA PANTOPRAZOLA), AND A PHARMACOLOGICALLY ACCEPTABLE EXCIPIENT. THE EXCIPIENT UNDERSTANDS A POLYMER THAT HAS MONOMERIC UNITS OF VIRYL PIRRILIDONE, SUCH AS POLYVINYL PIRROLIDONE OR A VIRYL VIRYL-ACETATE PIRROLIDONE COPOLYMER. SURPRISINGLY, IT HAS BEEN FOUND THAT THE VINILPIRROLIDONA POLYMER ACTS AS A STABILIZING EXCIPIENT ON THE SULFINYL BENCIMIDAZOLA REPLACED WITH PIRIDILE IN A WAY THAT THE COMPOSITION DOES NOT NEED TO INCLUDE ANY INCIDENT COMPONENT OF THE ASSETS. IN A PREFERRED EMBODIMENT, THE COMPOSITION IS IN THE FORM OF A CAPSULE, THROUGH WHAT THE MIXTURE OF THE BENCIMIDAZOLA OF SULFINILOR SUBSTITUTE PIRIDILO AND THE POLYMER OF PIRROLIDONE VINYL IN THE FORM OF A MIXED DUST OR GRANULAR COVER THE CAPSULE, THE COVER OF THE CAPSULE IS MADE FROM AN ENTERIC MATERIAL OR COVERED WITH AN ENTERIC MATERIAL. A PROCESS TO PREPARE THE STABLE PHARMACEUTICAL COMPOSITION IS ALSO PRESENTED.

Description

Oral and stable pharmaceutical composition that It contains a substituted pyridylsulfinyl benzimidazole.

Background of the invention

The present invention relates to a pharmaceutical composition, oral and stable, comprising a substituted pyridylsulfinyl benzimidazole, which, as an ingredient active, it has an acid secretion inhibitory activity gastric, and a base excipient that acts as an excipient stabilizer. The present invention also relates to a process for preparing said pharmaceutical composition.

In US Patents 4,255,431, 4,628,098 and 4,758,579 are disclosed pyridylsulfinyl benzimidazoles (such as omeprazole) as potent inhibitors of gastric acid secretion. This type of compound inhibits the gastric acid secretion inhibiting the activity of the H + - K + adenosine triphosphatase (pump protons) A well known fact is that drugs of this type They are very unstable in an acidic environment. They are also unstable in presence of organic solvents and moisture. Therefore, the formulation with which these drugs are administered to the patient and the manufacturing process of said formulation should be designed in such a way that the drug is protected against moisture and acidic media Because the drug degrades very quickly in the acidic fluids of the digestive system, the formulations must also have an enteric coating.

US Patent 4,786,505 discloses a oral pharmaceutical composition comprising a core, which contains omeprazole and an alkaline reaction compound or an alkaline salt of omeprazole optionally mixed with an alkaline compound; one or several internal coating layers, comprising compounds inert that are soluble in water or disintegrate rapidly in water or comprising polymeric and water soluble compounds that they form films, optionally comprising said layers alkaline compounds that stabilize the pH; and a coating enteric external The alkaline reaction compound consists of a substance (or various substances) pharmaceutically acceptable (s) that generates (n) a "micro-pH" around each particle of omeprazole, the pH being not less than 7 and preferably not less than 8 when water is adsorbed in the particles of the mixture or when small amounts of water are added to the mixture. The layer Internal coating separates the core, which contains the omeprazole, of the coating polymer (s) enteric comprising (n) free carboxyl groups. The enteric coating polymers could otherwise cause degradation of omeprazole during the procedure of coating or during storage.

Japanese patent 05-194.225 exposes formulations in the form of tablets, granules and capsules, in which benzimidazole inhibitors suitable for ulcers gastric stabilize by mixing them with amino acids and pH stabilizers.

U.S. Patent 5,385,739 discloses a stable microgranule formulation comprising a neutral core of sugar and starch, and an active layer formed by a solution of omeprazole in mannitol in essentially equal amounts, said active layer of omeprazole comprising approximately 10% in carboxymethyl starch weight and about 5% by weight of sodium lauryl sulfate, said omeprazole solution being applied in Mannitol to the neutral core using hydroxypropyl methylcellulose as high viscosity binder.

In PCT patent application WO 97/12581 Int. A composition is presented comprising: (a) a central part containing omeprazole as the active substance, which consists central part in cores, having mixed first and compressed subsequently the active substance of omeprazole, not due find said active substance of omeprazole in the form of a salt alkaline; (b) an intermediate layer; and (c) an enteric layer. The composition set forth in said document is described as a free composition of alkaline reaction compounds, which is They previously considered essential. However, the various  compositions exemplified in WO 97/12581 contain a lubricant, such as sodium stearyl fumarate, magnesium stearate or talc in the core, or talc in the intermediate layer. Sayings Compounds are alkali metal salts or metals alkaline earth, which are usually considered alkaline type.

WO96 / 01623 discloses a form oral pharmaceutical composed of multiple compressed units, which comprises excipients for tablets and coated units individually of an enteric coating, containing the core material active substances such as omeprazole mixed optionally with alkaline compounds coated with one or more layers, consisting of at least one of them in a layer of enteric coating The patent application does not expose the use of Polyvinylpyrrolidone as a stabilizing agent for omeprazole. He Example 8 of the application exposes a composition that contains omeprazole and polyvinylpyrrolidone, the ratio of omeprazole to 6: 1 polyvinylpyrrolidone

U.S. Patent 5,178,867 describes a medication administration system comprising a compartment, a semipermeable wall, media on the wall for increase the passage of liquid in the pharmaceutical form, and a wall passageway to administer the drug the way Pharmaceutical The use of polyvinylpyrrolidone from a liquid fluxing agent in order to increase the amount of liquid What happens in the compartment. In addition, since the claims of the application are limited to cross-linked polyvinylpyrrolidine which it is not soluble in water, said polyvinylpyrrolidone cannot be used as a liquid melting agent.

In European patent application 0.519.365, describes an oral presentation of pantoprazole comprising a core, an intermediate layer and an external layer resistant to gastric juices

In the international patent application WO 97/12580 an oral composition comprising a core is described, which includes a labile acid benzimidazole, e.g. eg, pantroprazole, a intermediate layer and an enteric layer. Omeprazole is excluded expressly of the claims of said application.

An objective of the present invention is to provide an oral and stable pharmaceutical composition comprising a substituted pyridylsulfinyl benzimidazole, which, as an active ingredient, exhibits a gastric acid secretion inhibiting activity, and a base excipient whose composition does not include any compound
alkaline.

Another object of the present invention is to provide a process for preparing an oral and stable pharmaceutical composition in the form of a mixture containing a substituted pyridylsulfinyl benzimidazole and a base excipient, the mixture not being compressed in said process in order to obtain units of hard and intact core, filling capsules of an enteric coating or capsules of an enteric material with the mixture in the form of powder or granules instead. Once the capsules have dissolved, the drug particles disperse freely in the gastrointestinal fluid, the resulting dissolution and absorption rate
high.

Another objective of the present invention is to in providing a procedure for preparing a composition oral and stable pharmaceutical in the form of a mixture containing substituted pyridylsulfinyl benzimidazole, said process being simple, faster and cheaper than the procedures of the prior art

Summary of the invention

It was unexpectedly found that in a mixture, comprising a substituted pyridylsulfinyl benzimadazole and one or more polymers obtained by polymerization of monomers, being at least one of them vinyl pyrrolidone, the substituted pyridylsulfinyl benzimidazole. The mixture, even if it is free of alkaline reaction compounds, it does not present any change of color as usually observed in the compositions in which the Benzimidazole has suffered degradation.

The present invention provides by consequently a pharmaceutical composition that is stable and appropriate to be administered orally to a patient, comprising the Composition the mixture of a substituted pyridylsulfinyl benzimidazole, which has an acid secretion inhibitory activity gastric large enough to inhibit the secretion of gastric acids of said patient, and a base excipient pharmaceutically acceptable, said base excipient comprising at least one polymer consisting at least partially of monomeric units of vinyl pyrrolidone. The mixture also contains optionally other pharmaceutically acceptable excipients. The composition with which an enteric capsule is filled, that is, a capsule that is coated with an enteric polymer or that is made of an enteric polymer, it is preferably a composition in form of granules or a simple powder mixture of active ingredient and base excipient and, optionally, other excipients that you wish to include.

The present invention also provides a procedure for preparing a pharmaceutical composition that is stable and that is appropriate to be administered orally to a patient, the procedure comprising mixing a substituted pyridylsulfinyl benzimidazole, which has an activity inhibitor of gastric acid secretion, with an excipient of pharmaceutically acceptable base, said excipient comprising base at least one polymer, which consists of at least partially in monomeric units of vinyl pyrrolidone, and with other pharmaceutically acceptable excipients that are included optionally The mixture, which has the form of a simple mixture powdery, it is introduced into enteric capsules, that is, in capsules that are coated with an enteric polymer or that are Made of an enteric polymer. The powdery mixture can alternatively become granules with which the enteric capsules

As well as the procedures for preparing prior art compositions include conversion steps of a powder mixture in core units, such as granules, pellets or tablets, as well as a stage in which apply an internal coating on the core units, the procedure for the preparation of pharmaceutical compositions according to the present invention does not require said steps because the powdery mixture or granules are introduced in capsules enteric without compressing them in intact core units and without any application of internal coating layers. Further, as well as the core units of the compositions of the technique Above include several pharmaceutical excipients, the composition Pharmaceutical of the present invention may consist of a simple mixture of a substituted pyridylsulfinyl benzimidazole and one or more polymers obtained by polymerization of monomers, being therefore least one of them vinyl pyrrolidone. The preparation procedure of the present invention is therefore simple, faster and more economical than prior art procedures.

\ newpage
Detailed description of the invention

According to the present invention, pyridylsulfinyl substituted benzimidazole, which exhibits an inhibitory activity of gastric acid secretion, may be one of the following

(a) a substituted pyridylsulfinyl benzimidazole which presents the structure of the formula I indicated to continuation

one

in which R 1 and R 2 can be identical or different and each R1 and R2 is selected from the group consisting of hydrogen, halogen, carbomethoxy, carboethoxy, and alkanoyl, alkoxy or C 1-4 alkyl in any position; R 6 is selected from the group consisting of hydrogen, methyl and ethyl; R 3 and R 5 can be identical or different and are individually selected from the group consisting of hydrogen, methyl, methoxy, ethoxy, methoxyethoxy and ethoxyethoxy; and R 4 is a methoxy; or

(b) a substituted pyridylsulfinyl benzimidazole which presents the structure of formula II indicated to continuation

2

where R 1 is hydrogen, methoxy or trifluoromethyl; R 2 and R 3 are independently hydrogen or methyl; R 4 is a C 2-5 alkyl fluorinated; and n is equal to 0 or 1; or

(c) a substituted pyridylsulfinyl benzimidazole which presents the structure of formula III indicated to continuation

\ vskip1.000000 \ baselineskip

3

in which R1 is an alkyl C_ {1-3} replaced at least partially by fluorine or chlorodifluoromethyl; R2 is hydrogen, halogen, trifluoromethyl, C 1-3 alkyl or alkoxy C_ {1-3}, which may be partially or completely substituted by fluorine; or R1 and R2 together with the oxygen atom, to which R1 is linked, are alkylenedioxy C_ {1-2}, which may be partially or completely substituted by fluorine or chlorotrifluoroethylenedioxy; R 4 is C 1-3 alkoxy, one of R 3 and R 5 is C 1-3 alkoxy, while the other it is hydrogen or C 1-3 alkyl; and n is equal to 0 or one.

Examples of pyridylsulfinyl benzimidazoles substituted, which can be used as an active ingredient in novel compositions of the present invention include the omeprazole, which is included in the definition of formula I, the lansoprazole, which is included in the definition of formula II, and the pantoprazole, which is included in the definition of formula III. The amount of active ingredient to be used in the composition is what provides an appropriate and therapeutically effective dose, it is that is, an amount sufficient to inhibit acid secretion gastric of a patient using a dosage regimen appropriate daily.

According to the present invention, the composition Pharmaceutical contains, in addition to pyridylsulfinyl benzimidazole substituted, a base excipient comprising one or more polymers obtained by polymerization of monomers, being by At least one of them vinyl pyrrolidone.

An example of one type of polymers that can be used in the present invention are polyvinylpyrrolidones also known by the name of povidone or PVP. In North American Pharmacopoeia XXII, povidone is described as a synthetic polymer that essentially comprises linear groups of 1-vinyl-2-pyrrolidone. Polyvinylpyrrolidones can usually be obtained from BASF, under the brand name Kollidon, or from ISP, under the brand name Plasdone. Polyvinylpyrrolidone can be obtained as a water soluble polymer or as a water insoluble crosslinked polymer. Examples of water soluble polyvinylpyrrolidones include PVP K-12, PVP K-15, PVP K-17, PVP K-25, PVP K-30, PVP K-60, PVP K-90 and PVP K-120, which they have respectively molecular weights of approximately 2500, 8000, 10000, 30000, 50000, 400000, 1000000 and 3000000. Soluble PVP is traditionally used as a binder in tablet formulations. In the present invention, soluble PVP is used in the novel composition as a stabilizing excipient

 \ hbox {and as a diluent of pyridylsulfinyl benzimidazole
replaced.} 

Cross-linked polyvinylpyrrolidone is a polymer which is obtained by a polymerization process that generates a physically crosslinked polyvinylpyrrolidine (patent American 3,933,766) which is insoluble in water and any usual solvent. Examples of cross-linked polyvinylpyrrolidones, which can be used in the present invention, include several classes such as those marketed by BASF under the brand names Kollidon CL, Crospovidone M and Kollidon CL-M. Because of his property of easily increase in volume, polyvinylpyrrolidone crosslinked is traditionally used in tablets as a disintegrating In the present invention, however, it is used as stabilizing excipient and as a diluent of pyridylsulfinyl substituted benzimidazole.

Another example of a type of polymers that can used in the present invention are the copolymers of vinyl pyrrilidone-vinyl acetate that are soluble in water and which are obtained by copolymerization of vinylpyrrolidone and vinyl acetate. An example of a copolymer of vinyl pyrrolidone-vinyl acetate, which can be used in the present invention, it is the copilomer that BASF markets with the brand name Kollidon VA-64. At the moment invention, the co-polymer of Vinylpyrrolidone-Vinyl Acetate is used as stabilizing excipient and as a diluent of pyridylsulfinyl substituted benzimidazole.

According to the present invention, the excipient of Pharmaceutically acceptable base is included in an amount between approximately 10% and approximately 98%, preferably between about 50% and about the 90% by weight with respect to the total weight of the composition.

According to the present invention, the pharmaceutical composition may also include other conventional excipients that are pharmaceutically acceptable. In the Handbook of Pharmaceutical Excipients manual (Ed. A. Wade and PJ Weller, The Pharmaceutical Press, London), in the list of inactive ingredients of the US FDA health authority, as well as in other sources of pharmaceutical literature you can find various enumerations of pharmaceutical excipients that are well known in the pharmaceutical art.

In preferred embodiments, the pharmaceutically acceptable excipients may comprise fatty acid glycerides. An example of acid glycerides fatty, which can be used in the present invention, is a mixture of glycerides (e.g., mono, di- and / or triglyceride) of acids fatty ones that have long chains (e.g., C12-C18); for example, the range of products marketed under the name of Gelucine brand (Gattefosse Corporation). Another example of glycerides of fatty acids, which can be used in the present invention, is a mixture of fatty acid glycerides (e.g., triglycerides) that have medium length chains (e.g., C 8 - C 10); for example, the range of products that are marketed with the brand names MiglYol, Crodamol GTC / C, MCT oil, Neobee M5, AKOMED, Nesatol, and others similar. Acid glycerides Fatty included in the composition of the present invention may be also vegetable oils, such as castor oil, oil hydrogenated castor, or hydrogenated glycerides of plant origin, such as those sold under the brand name Witepsol.

According to the procedure for preparing the In the present invention, a pyridylsulfinyl benzimidazole is mixed substituted, which exhibits a secretory inhibitory activity of gastric acids, the base excipient, which comprises one or more polymers comprising vinyl pyrrolidone monomer units, and optionally other pharmaceutically acceptable excipients, with in order to obtain a mixture or granules, introducing the mixture or the granules thus obtained in capsules, being coated to then the capsules filled with an enteric coating, or by introducing the mixture or granules into capsules that have an enteric coating or are made of a enteric material In the embodiments in which one of the pharmaceutically acceptable excipients is a glyceride of fatty acids, a liquid fatty acid glyceride is mixed with the other ingredients of the composition, or first heated a solid fatty acid glyceride above its temperature of melting, and then the liquid obtained is mixed with the other ingredients of the composition in order to obtain granules.

The capsules, which can be used in the present invention, can be hard or soft capsules. The outer shell of the capsules can be made of plasticizers, water and an agent or agents that facilitate film formation. The envelope may also contain dyes and opacifying agents. Examples of agents that facilitate film formation and that can be used in the capsule wrap include gelatin, methylcellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, and the like. If the wrap is of the conventional type, p. For example, it is made of gelatin, the envelope of an enteric outer layer is coated. The capsules may alternatively consist of enteric capsules, in which the envelope itself is enteric. The envelope of the enteric capsules can be made of one or more polymers that easily form films, at least one of them being enteric. The composition of enteric capsules is well known in the art. For example, the envelope may be made of a mixture of polymers, such as gelatin or hydroxypropyl methylcellulose, and one or more enteric polymers, such as an enteric polyacrylate polymer, cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate or cellulose acetate butyrate ; or of a mixture of gelatin or hydroxypropyl methylcellulose and polyvinyl acetate phthalate; or calcium alginate and the like. Enteric polymers may be in the form of free acids or corresponding salts. When the wrap is of the conventional type, an outer layer of enteric coating can be applied using known techniques. The coating composition may be based on an aqueous or organic solvent. Drying of the applied coating layers

 \ hbox {can
be performed using conventional means or in the
empty.} 

In another embodiment of the procedure of the present invention, a pyridylsulfinyl benzimidazole is mixed substituted, which exhibits a secretory inhibitory activity of gastric acids, the base excipient, comprising one or various polymers of vinyl pyrrolidone, and optionally others pharmaceutically acceptable excipients, in order to obtain a powdery mixture, then submitting the mixture thus obtained at conventional processing stages in order to obtain granules or tablets.

The following illustrates in more detail the present invention by the following examples.

Example 1

Omeprazole and polyvinylpyrrolidone were mixed crosslinked in the amounts indicated in Table 1. It was introduced the mixture thus obtained in capsules.

TABLE 1

Ingredient Weight (mg / capsule) Omeprazole  \; 20.00 Cross-linked polyvinylpyrrolidone (Kollidon CL-M) 100.00 Total 120.00

The capsules were coated in a coating of Freund (Hi-Coater) with an enteric layer that implied an increase in weight of 10%, the composition of the coating indicated in Table 2.

TABLE 2

Ingredient Weight (g) Eudragit L - 100 - 55 100.00 Sodium hydroxide 1.40 Titanium dioxide 1.70 talcum powder 50.00 Polyethylene Glycol - 300 20.00 Water 650.00

Example 2

Omeprazole and a copolymer of vinyl pyrrolidone-vinyl acetate in the amounts indicated in Table 3. The mixture thus obtained was introduced into capsules

TABLE 3

Ingredient Weight (mg / capsule) Omeprazole  \; 20.00 Vinyl Pyrrolidone Copolymer - Vinyl Acetate (Kollidon VA-64) 100.00 Total 120.00

The capsules were coated in a coating of Freund (Hi-Coater) with an enteric layer that implied an increase in weight of 10%, the composition of the coating indicated in Table 2.

Example 3

Omeprazole, a copolymer of vinyl pyrrolidone-vinyl acetate and polyvinyl pyrrolidone crosslinked in the amounts indicated in Table 4. It was introduced the mixture thus obtained in capsules.

\ vskip1.000000 \ baselineskip
TABLE 4

Ingredient Weight (mg / capsule) Omeprazole 20.00 Cross-linked polyvinylpyrrolidone (Kollidon CL-M) 50.00 Copolymer of vinyl pyrrolidone - vinyl acetate (Kollidon VA-64) 50.00 Total 120.00 \;

\ vskip1.000000 \ baselineskip

The capsules were coated in a coating of Freund (Hi-Coater) with an enteric layer that implied an increase in weight of 10%, the composition of the coating indicated in Table 2.

Example 4

Omeprazole and polyvinylpyrrolidone were mixed (PVP K 30) in the amounts indicated in Table 5. It was introduced the mixture thus obtained in capsules.

\ vskip1.000000 \ baselineskip
TABLE 5

Ingredient Weight (mg / capsule) Omeprazole  \; 20.00 PVP K30 100.00 Total 120.00

\ vskip1.000000 \ baselineskip

The capsules were coated in a coating of Freund (Hi-Coater) with an enteric layer that implied an increase in weight of 10%, the composition of the coating indicated in Table 2.

Example 5

Omeprazole and the other ingredients were mixed in the amounts indicated in Table 6. The mixture was introduced thus obtained in capsules.

\ vskip1.000000 \ baselineskip
TABLE 6

Ingredient Weight (mg / capsule) Omeprazole 20.00 Kollidon CL-M 50.00 Avicel PH 112 50.00 Total 120.00 \;

The capsules were coated in a coating of Freund (Hi-Coater) with an enteric layer that It implied a 10% increase in weight.

Example 6

Omeprazole and Kollidon were mixed CL-M in the amounts indicated in Table 7. It heated for 20 minutes AKOMED R (fatty acid glyceride comprising caprylic / capric triglycerides and which are obtained of coconut and / or palm oils) and Glucerire 33/01 (a mixture of glycerides, p. eg, mono-, di- and / or triglycerides of fatty acids long chain) at a temperature of 60 ° C, stirred well and cooled to 30 ° C. The mixture of omeprazole and Kollidon was granulated with The liquid mixture. The granules were screened using a sieve with No. 22 mesh and they were introduced into capsules. The capsules were coated in a Freund coater (Hi-Coater) with an enteric layer that involved a 10% increase in weight, the coating composition being the one indicated in Table 2.

\ vskip1.000000 \ baselineskip
TABLE 7

Ingredient Weight (mg / capsule) Omeprazole 20.00 Cross-linked polyvinylpyrrolidone (Kollidon CL-M) 100.00 \; Gelucire 33/01 10.00 AKOMED R 20.00 Total 150.00 \;

\ vskip1.000000 \ baselineskip

The capsules of examples 1-6, already equipped with the enteric coating, they underwent a test according to the indications of the dissolution test (procedure B) for pharmaceutical forms (with enteric coating) of delayed release described in the US pharmacopoeia XXIII, page 1795. During the acid stage, no release was released. Omeprazole capsules. The percentage values of the released quantities that were obtained during the stage buffer are indicated in Table 8.

\ vskip1.000000 \ baselineskip
TABLE 8

Weather Average cumulative percent released (minutes) Ex.1 Ex.2 Ex.3 Ex.4 Ex.5 Ex. 6 twenty 6.50 21.60 58.40 14.70 1.70 72.20 30 46.70 39.50 83.66 30.00 4.80 102.00 Four. Five 91.50 60.10 95.60 75.00 84.90 106.80

\ vskip1.000000 \ baselineskip

In another test, the capsules in the examples 1-6, already equipped with the enteric coating, is kept in high density polyethylene bottles at 45 ° C and 75% RH (relative humidity). The pharmaceutical compositions, which they contained the enteric capsules, they did not present any indication of instability, such as changes in color or appearance, as can be seen in Table 9

TABLE 9

Example No. Observations 15 days, 40 ° C / 75% RH 30 days, 40ºC / 75% RH one No change No change 2 No change No change 3 No change No change 4 No change No change 5 No change No change 6 No change No change

Omeprazole content was determined, which was I was in the capsules stored for 30 days in the conditions indicated above, using a procedure of high performance liquid chromatography that allows to evaluate the stability. Table 10 presents the results. corresponding.

TABLE 10

Example No. Test one 105.10 2 100.19 3 99.85 4 99.66 5 98.07 6 95.20

For purely illustrative reasons, it has been described the present invention with reference to forms of concrete realization. The embodiments presented admit nevertheless numerous variations that are evident for a skilled in the art and fall within the scope of the invention claimed in this document.

Claims (12)

1. Pharmaceutical composition that is stable and appropriate to be administered orally to a patient, said composition comprising a mixture of omeprazole, which exhibits an inhibitory activity of gastric acid secretion and is included in an amount sufficient to inhibit the secretion of gastric acids in said patient, and a pharmaceutically acceptable base excipient, comprising crosslinked polyvinylpyrrolidone, said mixture being inside a capsule shell, said envelope being coated with an enteric material or said envelope being an enteric material, said composition being characterized in that said base excipient comprises about 10% to about 98% by weight of said mixture.
2. Composition according to claim 1, said base excipient comprising approximately 50% a approximately 90% by weight of said mixture.
3. Composition according to claim 1, said mixture further comprising an acid glyceride fatty
4. Composition according to claim 1, being said mixture contained in the form of a powdery mixture in the inside said capsule shell.
5. Composition according to claim 1, being said mixture contained in the form of granules inside said capsule wrap
6. Method for preparing a stable pharmaceutical composition that is suitable for oral administration, the composition comprising a mixture of omeprazole, which exhibits an inhibitory activity of gastric acid secretion and which has been included in an amount sufficient to inhibit the secretion of gastric acids in said patient, and about 10% to about 98% by weight of a pharmaceutically acceptable base excipient, said crosslinked polyvinylpyrrolidone base excipient, said mixture being contained within a capsule shell that is coated of an enteric material or that is made of an enteric material, said process being characterized in that said base excipient comprises about 10% to about 98% by weight of said mixture, because the process comprises the mixture of omeprazole, which has an inhibitory activity of acid secretion and that has been included in an amount sufficient to inhibit the secretion of gastric acids in a patient, with a pharmaceutically acceptable base excipient, comprising cross-linked polyvinylpyrrolidone, in order to obtain a mixture, and the introduction of said mixture into Capsule wraps that are coated with an enteric material or are made of an enteric material.
7. Method according to claim 6, the process further comprising mixing at least one pharmaceutically acceptable excipient in said mixture.
8. Method according to claim 7, said pharmaceutically acceptable excipient consisting of a fatty acid glyceride.
9. Method according to claim 6, the process comprising introducing said mixture into powdery mixture form in a capsule made of a material enteric.
10. Method according to claim 6, the process comprising the coating of the envelope of a capsule with an enteric material and the introduction of said mixture in the form of a powder mixture in said envelope.
11. Method according to claim 6, the process comprising the granulation of said mixture at in order to obtain granules and the introduction of said granules in the wrap of a capsule made of enteric material.
12. Method according to claim 6, the process comprising the granulation of said mixture at In order to obtain granules, the coating of the envelope of a capsule with enteric material and the introduction of said granules in said envelope.
ES98123251T 1998-05-28 1998-12-07 Oral and stable pharmaceutical composition containing a replaced benzimidazol pyridilsulfinil. Expired - Lifetime ES2256910T3 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US8622498A true 1998-05-28 1998-05-28
US86224 1998-05-28

Publications (1)

Publication Number Publication Date
ES2256910T3 true ES2256910T3 (en) 2006-07-16

Family

ID=22197118

Family Applications (1)

Application Number Title Priority Date Filing Date
ES98123251T Expired - Lifetime ES2256910T3 (en) 1998-05-28 1998-12-07 Oral and stable pharmaceutical composition containing a replaced benzimidazol pyridilsulfinil.

Country Status (11)

Country Link
US (1) US20020128293A1 (en)
EP (1) EP0960620B1 (en)
CN (1) CN1136850C (en)
AT (1) AT315396T (en)
AU (1) AU1979699A (en)
BR (1) BR9910723A (en)
DE (1) DE69833157T2 (en)
ES (1) ES2256910T3 (en)
RU (1) RU2216321C2 (en)
WO (1) WO1999061022A1 (en)
ZA (1) ZA9810765B (en)

Families Citing this family (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020039597A1 (en) * 1998-04-20 2002-04-04 Koji Ukai Stabilized compositions containing benzimidazole-type compounds
IL130602D0 (en) * 1999-06-22 2000-06-01 Dexcel Ltd Stable benzimidazole formulation
ES2168043B1 (en) 1999-09-13 2003-04-01 Esteve Labor Dr Pharmaceutical form oral solid modified release containing a composite of bencimidazol labil in the middle acid.
EP1221947B1 (en) * 1999-10-01 2004-12-08 Natco Pharma Limited Soft gel capsule resistant to gastric juices
CA2387746C (en) * 1999-10-20 2010-06-29 Koji Ukai Methods for stabilizing benzimidazole-based compounds
SI20720A (en) * 2000-11-20 2002-06-30 LEK, tovarna farmacevtskih in kemičnih izdelkov, d.d. New pharmaceutical preparation in the form of cellulose capsules applicable to derivatives of benzimidazole
US20030050620A1 (en) * 2001-09-07 2003-03-13 Isa Odidi Combinatorial type controlled release drug delivery device
US6620900B2 (en) * 2002-02-07 2003-09-16 Isp Investments Inc. Proliferous copolymer of vinyl pyrrolidone and vinyl acetate
DE10247037A1 (en) * 2002-10-09 2004-04-22 Abbott Gmbh & Co. Kg Solid, rapid release dosage form, especially for sparingly soluble drugs, obtained by forming and cooling softened, shapable mixture of crosslinked non-thermoplastic carrier, adjuvant and active agent
MY148805A (en) 2002-10-16 2013-05-31 Takeda Pharmaceutical Controlled release preparation
PE20050150A1 (en) 2003-05-08 2005-03-22 Altana Pharma Ag A dosage form comprising (s) as active ingredient -pantoprazol
CL2004000983A1 (en) * 2003-05-08 2005-03-04 Altana Pharma Ag oral pharmaceutical composition in tablet form comprising pantoprazole magnetic dihydrate, wherein the tablet form is composed of a core, an intermediate layer and an outer layer; and use of the pharmaceutical composition in ulcers and
WO2004112756A1 (en) 2003-06-26 2004-12-29 Isa Odidi Proton pump-inhibitor-containing capsules which comprise subunits differently structured for a delayed release of the active ingredient
US20050042277A1 (en) * 2003-07-17 2005-02-24 Irukulla Srinivas Pharmaceutical compositions having a swellable coating
CA2540105A1 (en) * 2003-09-25 2005-03-31 Natco Pharma Limited Enteric soft gelatin capsule containing esomeprazole and method of preparation
TWI372066B (en) 2003-10-01 2012-09-11 Wyeth Corp Pantoprazole multiparticulate formulations
WO2005051362A2 (en) * 2003-11-28 2005-06-09 Ranbaxy Laboratories Limited Oral benzimidazole compositions comprising an active core, an optional separating layer and an enteric coating
JP5563735B2 (en) 2004-06-16 2014-07-30 タケダ ファーマシューティカルズ ユー.エス.エー. インコーポレイティド PPI multiple dosage form
US8394409B2 (en) 2004-07-01 2013-03-12 Intellipharmaceutics Corp. Controlled extended drug release technology
US8658216B2 (en) 2004-12-23 2014-02-25 Ranbaxy Laboratories Limited Stable oral benzimidazole compositions and process of preparation thereof
US20080279951A1 (en) * 2005-02-02 2008-11-13 Rajesh Gandhi Stable Oral Benzimidazole Compositions Prepared by Non-Aqueous Layering Process
US10064828B1 (en) 2005-12-23 2018-09-04 Intellipharmaceutics Corp. Pulsed extended-pulsed and extended-pulsed pulsed drug delivery systems
EP1965774A2 (en) * 2005-12-30 2008-09-10 Cogentus Pharmaceuticals, Inc. Oral pharmaceutical formulations containing non-steroidal anti-inflammatory drugs and acid inhibitors
CN101453993A (en) 2006-04-03 2009-06-10 伊萨·奥迪迪;阿米纳·奥迪迪 Controlled release delivery device comprising an organosol coat
US20140010860A1 (en) 2006-05-12 2014-01-09 Isa Odidi Abuse and alcohol resistant drug composition
SG172660A1 (en) * 2006-06-01 2011-07-28 Schering Corp Pharmaceutical compositions for sustained release of phenylephrine
JP2009538901A (en) * 2006-06-01 2009-11-12 デクセル ファーマ テクノロジーズ エルティーディー. Dual unit pharmaceutical formulation
KR20100116165A (en) 2007-10-12 2010-10-29 다케다 파마슈티칼스 노쓰 어메리카, 인코포레이티드 Methods of treating gastrointestinal disorders independent of the intake of food
US8911787B2 (en) 2008-02-26 2014-12-16 Ranbaxy Laboratories Limited Stable oral benzimidazole compositions and process of preparation thereof
EP2293782B1 (en) * 2008-05-06 2015-08-12 Dexcel Pharma Technologies Ltd. Stable benzimidazole formulation
EP2525783A1 (en) 2010-01-18 2012-11-28 Cephalon France Improved oral lysophilisates containing pvp/va
CN102940611B (en) * 2012-11-26 2017-02-22 康普药业股份有限公司 Esomeprazole magnesium contained enteric-coated tablet
EP3065720A1 (en) * 2013-11-04 2016-09-14 Capsugel Belgium NV Methods and systems for improved bioavailability of active pharmaceutical ingredients including esomeprazole
CA2964628A1 (en) * 2014-10-20 2016-04-28 Pharmaceutical Manufacturing Research Services, Inc. Extended release abuse deterrent liquid fill dosage form
US10076494B2 (en) 2016-06-16 2018-09-18 Dexcel Pharma Technologies Ltd. Stable orally disintegrating pharmaceutical compositions

Family Cites Families (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3216579A (en) * 1961-05-25 1965-11-09 Ind Biology Lab Inc Water-insoluble polyvinylpyrrolidone composition
US4139688A (en) * 1977-06-24 1979-02-13 Gaf Corporation Preparation of insoluble polyvinylpyrrolidone
US4180633A (en) * 1977-06-24 1979-12-25 Gaf Corporation Preparation of insoluble polyvinylpyrrolidone
SE7804231A (en) * 1978-04-14 1979-10-15 Haessle Ab Gastric acid secretion Mediterranean
DE2942657A1 (en) * 1979-10-22 1981-04-30 Basf Ag A process for preparing vinylpyrrolidone polymer whose aqueous solution has a high viscosity, by Heat Treatment of aqueous solutions of conventional polyvinyl pyrrolidone
IL75400A (en) * 1984-06-16 1988-10-31 Byk Gulden Lomberg Chem Fab Dialkoxypyridine methyl(sulfinyl or sulfonyl)benzimidazoles,processes for the preparation thereof and pharmaceutical compositions containing the same
JPH0244473B2 (en) * 1984-08-16 1990-10-04 Takeda Chemical Industries Ltd Pirijinjudotaioyobisonoseizoho
GB2189698A (en) * 1986-04-30 1987-11-04 Haessle Ab Coated omeprazole tablets
US5073614A (en) * 1990-10-18 1991-12-17 Isp Investments Inc. Strongly swellable, moderately crosslinked polyvinylpyrrolidone
YU48263B (en) * 1991-06-17 1997-09-30 Byk Gulden Lomberg Chemische Fabrik Gmbh. A process for making a pharmaceutical preparation based on pantoprazole
US5178867A (en) * 1991-08-19 1993-01-12 Alza Corporation Dosage form for delivering drug in short-time period
FR2692146B1 (en) * 1992-06-16 1995-06-02 Ethypharm Sa omeprazole stable compositions of microgranules of gastro-protected and process for obtaining them.
US5252611A (en) * 1992-07-20 1993-10-12 Isp Investments Inc. Controlled release tablets including strongly swellable, moderately crosslinked polyvinylpyrrolidone
EE03305B1 (en) * 1994-07-08 2000-12-15 Astra Aktiebolag The multiple unit tableted dosage form I.
ES2094694B1 (en) * 1995-02-01 1997-12-16 Esteve Quimica Sa New pharmaceutically stable of a benzimidazole compound formulation and production process.
DE69628444D1 (en) * 1995-09-21 2003-07-03 Pharma Pass Ii Llc Pharmaceutical composition containing acidable omeprazole and method for the production thereof
US6096340A (en) * 1997-11-14 2000-08-01 Andrx Pharmaceuticals, Inc. Omeprazole formulation
SE9704869D0 (en) * 1997-12-22 1997-12-22 Astra Ab New pharmaceutical formulaton II
DK173431B1 (en) * 1998-03-20 2000-10-23 Gea Farmaceutisk Fabrik As A pharmaceutical formulation comprising a 2 - [[(2-pyridinyl) methyl] sulfinyl] benzimidazole having anti-ulcer activity, and front transition
US6228400B1 (en) * 1999-09-28 2001-05-08 Carlsbad Technology, Inc. Orally administered pharmaceutical formulations of benzimidazole derivatives and the method of preparing the same

Also Published As

Publication number Publication date
AU1979699A (en) 1999-12-13
CN1136850C (en) 2004-02-04
EP0960620B1 (en) 2006-01-11
ZA9810765B (en) 1999-08-06
BR9910723A (en) 2001-06-12
EP0960620A1 (en) 1999-12-01
DE69833157T2 (en) 2006-08-31
US20020128293A1 (en) 2002-09-12
AT315396T (en) 2006-02-15
RU2216321C2 (en) 2003-11-20
WO1999061022A1 (en) 1999-12-02
DE69833157D1 (en) 2006-04-06
CN1237415A (en) 1999-12-08

Similar Documents

Publication Publication Date Title
DE69630286T2 (en) Dosage forms composed from several units containing a proton pump inhibitor
RU2205028C2 (en) Oral pharmaceutical medicinal form with discrete release
FI101598B (en) Process for oral medicinal products containing the pantoprazole mfd istamiseksi
US6780435B2 (en) Omeprazole formulation
EP0247983B1 (en) New pharmaceutical preparation for oral use
DE69721845T2 (en) Oral morphin preparation in particulate shape
US4894240A (en) Controlled absorption diltiazem formulation for once-daily administration
JP4649001B2 (en) Omeprazole formulation
CA2114014C (en) Advanced drug delivery system and method of treating psychiatric, neurological and other disorders with carbamazepine
US6515010B1 (en) Carvedilol methanesulfonate
CA2346988C (en) Pharmaceutical formulation comprising omeprazole
EP1078628B1 (en) Multiple unit tableted dosage form
EP0814839B1 (en) Oral pharmaceutical dosage forms comprising a proton pump inhibitor and a nsaid
EP1276469B1 (en) Taste masking coating composition
KR100755154B1 (en) Oral Pharmaceutical Extended Release Dosage Form
JP4901727B2 (en) Coated tablet formulation and method
US5616345A (en) Controlled absorption diltiazen formulation for once-daily administration
CN1152671C (en) Multiple unit pharmaceutical preparation containing proton pump inhibitor
EP0249587B1 (en) Solid pharmaceutical preparation with extended release and process for its preparation
CN1227004C (en) Partial fatty acid oxidation inhibitors in treatment of congestive heart failure
ES2410812T5 (en) Controlled release preparation
EP0311582A1 (en) Pharmaceutical preparation with extended release of a dihydropyridine and a beta-adrenoreceptor antagonist and a process for the preparation thereof
DE69631981T2 (en) Lansoprazole-containing drug composition and method of preparation
JP2012525444A (en) Orally disintegrating tablet composition comprising a combination of high and low dose drugs
RU2179453C2 (en) Peroral pharmaceutical medicinal forms including proton pump inhibitor and antacid substance or alginate